Abstract
Whether antiretroviral therapy (ART) is always completely suppressive, or HIV might continue to replicate at low levels despite ART in some people with HIV (PWH), is still debated. Here, we intensified the ART regimen by doubling dolutegravir (DTG) dosage and investigated the impact of this strategy on HIV blood and tissue reservoirs, immune activation, and inflammation. Twenty HIV-infected adults, who had received a triple ART consisting of 50mg DTG/600 mg abacavir/300 mg lamivudine pre-intensification and had been suppressed on ART for at least two years, were enrolled in a phase 2 randomized clinical trial. Half of them received an additional 50 mg of DTG for a period of 84 days. As expected, plasma and tissue DTG concentrations significantly increased during the study period in the intensified group but not in the control group. Accordingly, significant decreases in total HIV DNA, intact HIV DNA, and cell-associated unspliced (US) HIV RNA in PBMCs, as well as in the US RNA/total DNA ratio, were observed in the intensified group but not in the control group. Intensification also modestly reduced markers of immune activation and exhaustion but had no measurable impact on systemic or tissue inflammation. Together with this, intensification resulted in a temporary decrease in the CD4/CD8 ratio that returned to baseline by day 84. Our results strongly suggest that the pre-intensification ART regimen was not completely suppressive. If confirmed in larger clinical trials, these results could have an impact on the clinical management of PWH and HIV curative strategies.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Trial
NCT05351684
Funding Statement
C.F.L. is a FRIA grantee of the Belgian Fund for Scientific Research (Fonds de la Recherche Scientifique, FNRS) and is supported by the Fondation Leon Fredericq. This work was supported in part by grant R01-AI124965 (to C.V.F.) from the US National Institutes of Health. A.O.P. acknowledges grant support from amfAR, The Foundation for AIDS Research (grant no. 1110680 77 RPRL), and from Partnership NWO-Dutch AIDS Fonds HIV cure for everyone (grant no. KICH2.V4P.AF23.001). G.D. is supported by the Belgian Fund for Scientific Research (Fonds de la Recherche Scientifique; FNRS).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The study was approved by the Liège University Hospital-Faculty Ethics Committee (Comité d’Éthique Hospitalo-Facultaire Universitaire de Liège, 2018/228). Prior to inclusion in the study, each participant had dated and signed an informed consent form.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
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Footnotes
This revised version of the manuscript incorporates the changes requested by the journal.
Data Availability
All data supporting the findings of this study are available within the paper and its Supplementary Information.
